Project Summary/Abstract Millions of Americans suffer from panic disorder, which is characterized by spontaneous and unexpected occurrences of panic attacks. Patients experiencing panic attacks repeatedly report a persistent and prompt urge to flee despite being in a safe, non-threatening environment such as the patient's home. However, the underlying mechanisms of panic are unknown and treatments are often ineffective. Panic is commonly modelled by escape elicited by imminent threats in rodents. Accordingly, escape-inducing circuits in mice induce panic in humans. Indeed, electrical stimulation of the dorsal periaqueductal grey (dPAG) induces panic in humans and escape in rodents. However, it is unknown how input from other regions to the dPAG modulate panic-related escape. The dorsal premammillary nucleus (PMd) is the largest input to the panicogenic dPAG, suggesting the PMd may have an important role in panic. However, the function of the PMd remains unknown. We now show PMd activation induces hallmark panic-related phenotypes, including escape and tachycardia. We hypothesize the PMd-dPAG projection is critical for enabling panic-related escape from threats. We developed a novel assay that exposes mice to a live predator (a rat) in close proximity without a separating barrier to induce naturalistic panic-related escape. In Aim 1, I will optogenetically activate and inhibit the PMd- dPAG projection to test if activity in this circuit is, respectively, sufficient and necessary for panic-related escape. In Aim 2, I propose to record PMd activity during exposure to a live predator to observe if increased PMd activity measured by fiber photometry predicts escape and possibly other defensive behaviors. Finally, in Aim 3, since our preliminary data show that dPAG neuronal activity correlates with panic-related escape, I will inhibit upstream PMd activity while performing in vivo calcium imaging in the dPAG to test if PMd input is necessary for accurate dPAG population encoding of escape. These Aims will be the first to demonstrate that the PMd is a key, but previously unrecognized, node in the panic network that may be a potential target for future panicolytic therapies. With the support of sponsoring and collaborating faculty from the Departments of Psychology, Neurology, and Electrical Engineering at the University of California, Los Angeles, execution of these Aims will provide advanced technical training on several sophisticated, cutting-edge techniques that enable the perturbation and monitoring of neural circuitry. Furthermore, the proposed training plan, carefully conceived by the sponsoring faculty, identifies several key Intellectual and Professional goals and concrete benchmarks that will form the foundation for a well-rounded, comprehensive scientific training and successful research career.